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Lenalidomide maintenance prolongs PFS in high-risk CLL
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SAN DIEGO — Lenalidomide maintenance appeared feasible and extended PFS among patients with high-risk chronic lymphocytic leukemia who had minimal residual disease after undergoing chemoimmunotherapy, according to findings of the CLLM1 study from the German CLL Study Group presented at the ASH Annual Meeting and Exposition.
Genetic markers and minimal residual disease (MRD) assessment can identify patients with CLL who have a poor outcome with first-line chemoimmunotherapy. Anna Maria Fink, MD, of the department of internal medicine and Center of Integrated Oncology Cologne-Bonn at University Hospital of Cologne in Germany, and colleagues evaluated lenalidomide (Revlimid, Celgene) maintenance therapy to target MRD in patients with CLL who had reached at least a partial response to first-line chemoimmunotherapy.
“This study was initiated to show the value of maintenance with lenalidomide after chemoimmunotherapy,” Fink said. “The rationale is based on previous analyses of CLL showing that about 30% of patients did not substantially benefit from chemotherapy only.”
PFS served as the primary outcome measure.
Researchers defined high-risk patients as those with MRD levels of 10-2 or higher, or MRD levels of 10-4 to less than 10-2 plus either an unmutated IGHV gene status, deletion 17p or TP53 mutation.
Out of an initial cohort of 468 patients from 62 sites, the researchers randomly assigned 89 patients (median age, 64; range, 32-80; 85.2% men) who had MRD (high, 37%; intermediate, 63%) after four cycles of chemoimmunotherapy to lenalidomide maintenance (n = 60) or placebo (n = 29). At baseline, 11.4% of patients had 17p deletion, 20.5% had a TP53 mutation, and 90.2% had an unmutated IGHV gene status.
Patients received 5 mg lenalidomide in the first cycle and were subsequently elevated to 15 mg by the seventh cycle. Treatment continued until disease progression.
“The dose escalations were guided by MRD assessments,” Fink said. “Eighty percent of patients in the lenalidomide arm escalated to 10 mg. However, less than half of patients reached the target dose.”
Patients underwent a median of 11.1 cycles (range, 0-42) of lenalidomide and 8.3 cycles (range, 1-35) of placebo. The median daily dose was 9.1 mg for both arms.
Median observation time was 17.7 months.
Results showed median PFS was not reached in the study drug arm and was 13.3 months for placebo (HR = 0.148). The P value of .00001 met the study’s determined efficacy boundary of .0006.
There was one death in the lenalidomide arm and two deaths in the placebo arm (HR for OS = 0.26).
“This was not statistically significant,” Fink said. “But with only three events, there are not enough data.”
The discontinuation rate was 42.9% in the lenalidomide arm and 72.4% in the placebo arm. Discontinuation occurred due to adverse events (n = 17 vs. 6), disease progression (n = 4 vs. 13), withdrawal of consent (n = 4 vs. 2) and other reasons (n = 2 for both arms).
Adverse events occurred in 32.1% of patients treated with lenalidomide and 20.7% treated with placebo. Grade 3 events occurred in 13% of the cohort, and less than 1% experience grade 4 events.
A greater proportion of patients treated with lenalidomide experienced neutropenia (30.4% vs 3.4%), gastrointestinal disorders (55.4% vs 27.6%), nervous system disorders (30.4% vs 13.8%), respiratory disorders (35.7% vs 13.8%) and skin disorders (60.7% vs 27.6%). Infections (50% vs 62.1%) and vascular disorders (14.3% vs 17.2%) occurred in more patients treated with placebo.
“Most events were mild or moderate,” Fink said. “Infections and gastrointestinal disorders, along with skin disorders were the main adverse events in this study. Vascular disorders also are reported.”
Researchers noted that conversion to MRD negativity only occurred on the lenalidomide arm.
“We observed a steady increase in the number of patients with high MRD levels in the placebo arm,” she said. “In contrast, the increase of MRD was slowed down in the lenalidomide arm. A small proportion of patients converted to MRD negativity.
“Patients with a median MRD level at baseline had a better outcome than patients with higher MRD levels,” Fink added.
An independent review confirmed robust, reliable and statistically significant data supporting the use of lenalidomide to prolong PFS in this setting, Fink said.
“The prognostic significance of MRD–based risk assessment was confirmed in this trial,” she said. – by Rob Volansky
For more information:
Fink AM, et al. Abstract 229. Presented at: The ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.
Disclosures: Fink reports travel grants, research funding and other support from AbbVie, Celgene, Mundipharma and Roche. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
Perspective
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Joshua Brody, MD
There were a lot of exciting protocols highlighted at this year’s ASH Annual Meeting and Exposition. One common theme was the emphasis of the potency of the immune system to try to keep patients’ hematologic malignancies at bay.
One great example of this with a powerful result is the German CLL Study Group. Patients with high-risk CLL — after standard upfront therapy with chemoimmunotherapy — were randomly assigned lenalidomide maintenance vs. placebo. They saw a dramatic result, with an 80% reduction in the risk for relapse among patients on lenalidomide maintenance. These are the highest-risk patients as defined by poor cytogenetics, positive minimal residual disease at the end of chemoimmunotherapy and IgVH mutational status.
To have a reduction in the risk of relapse — – especially with an agent that, as a single agent, has had only moderate benefit — is really adding another tool to the armamentarium. Quite honestly, the mechanism of these immunomodulatory drugs is still not completely clear, but the clinical result is very impressive and could be practice changing.
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